Histone deacetylase inhibitors based on derivatives of tricyclic polyhydroacridine and analogs possessing fused saturated five-and-seven-membered rings

ABSTRACT

The present invention refers to compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or chemoprevention of cancer hematological malignancy, proliferative diseases, neurological disorders and immunological disorders.

FIELD OF THE INVENTION

The present invention is related to new compounds derived from tricyclic1,2,3,4-tetrahydroacridine, 2,3-dihydro-1H-cyclopenta[b]quinoline,7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline,6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine and6,7,8,9-tetrahydrobenzo[b][1,7]naphthyridine for their use as inhibitorsof histone deacetylases and therapeutic agents for preventing ortreating malignancies associated with aberrant histone acetylation suchas cancer, hematological malignancies, proliferative diseases,neurological disorders, and immunological disorders.

BACKGROUND OF THE INVENTION

Histone deacetylases (HDACs) are enzymes that, as part of multiproteincomplexes or aggregates, catalyze the removal of acetyl groups fromε-NHAc lysine residues of histones and other proteins. These enzymeshave been classified into three distinct structural classes. Classes I,II and IV HDACs are zinc-dependent whereas Class III HDACs use NAD as acofactor. The biological functions of these classes of enzymes and thedifferent isoforms belonging to each class are known. Class I HDACsinclude HDAC 1, 2, 3, 4 and 8 and are related, among other functions,with proliferation, gene regulation, apoptosis, morphogenesis andtelomerase activity. Class IIa HDACs include HDAC 4, 5 and 7 and involvecardiac development, suppression of cardiac stress and regulation ofapopotosis. HDAC 6 is included in Class IIb and it has been associatedwith the status of tubulin and hsp90 acetylation (cf. W. Sippl and M.Jung, Eds. Epigenetic Targets in Drug Discovery, Wiley-VCH: Weinheim,2009). More recently, HDACs and their inhibitors have been associatedwith cell pluripotency, differentiation and reprogramming (cf. A.Kretsovali et al. Stem Cells International, 2012, Article ID 184154;doi: 10.1155/2012/184154).

The biological functions of HDACs have an extraordinary impact indiseases like cancer (L. Ellis and R. Pili, Pharmaceuticals 2010, 3,2441; L. Stimson et al. Annals of Oncology 2009, 20, 1293), centralnervous system disorders (cf. A. G. Kazantsev and L. M. Thomson, Nat.Rev. Drug Discov. 2008, 7, 854), inflammation and immunity (cf. M. R.Shakespear et al. Trends in Immunology 2011, 32, 335) and HIV-1 latency(cf. N. M. Archin et al. Nature 2012, 487, 482).

Within this context, HDAC inhibitors (HDACi) have emerged as veryrelevant and promising drugs for the treatment of cancer (cf. R. W.Johnstone, Nat. Rev. Drug. Discov. 2002, 1, 287; M. Dokmanovic et al.Mol. Cancer Res. 2007, 5, 981; S. Ropero and M. Esteller, Mol. Oncology2007, 1, 19). Although many of the actual mechanisms of anticanceractivity of HDACi are not completely understood, there is evidence thatthese compounds alter the biological machinery affecting the hallmarksof cancer like apoptosis (HDAC 1 and 2) differentiation (HDAC 3, 4, 5and 8), angiogenesis (HDAC 4, 6, 7 and 10), migration (HDAC 6),resistance to chemotherapy (HDAC 1) and proliferation (HDAC 1, 2, 3 and8) (cf. O. Witt et al. Cancer Lett. 2009, 277, 8).

Miller T. (Expert Opinion on Therapeutic Patents, Informa Healthcare, GB, 2004, 14(6), 791-804) and Curtin M. (Expert Opinion on TherapeuticPatents, Informa Healthcare, G B, 2002, 12(9), 1375-1384) describedifferent structural classes of known HDAC inhibitors that include thenon-peptidic hydroxamic acids, cyclic peptides, benzamides, butyric acidanalogues and electrophilic ketones.

Suberoylanilide hydroxamic acid (SAHA) was the first HDACi approved in2006 by the US FDA for the treatment of cutaneous T-cell lymphoma (CTCL)(cf. P. A. Marks, Oncogene 2007, 26, 1351; P. A. Marks, R. Breslow, Nat.Biotechnol. 2007, 25, 84). In 2009, disulfide FK228 gained approval bythe same American agency (cf. C. Grant et al. Expert Rev. AnticancerTher. 2010, 10, 997; E. M. Bertino et al. Expert Opin. Investig. Drugs2011, 20, 1151). Nowadays, many HDACi have been prepared, some of thembeing in clinical development (cf. T. A. Miller et al. J. Med. Chem.2003, 46, 5097; M. Paris et al. J. Med. Chem. 2008, 51, 1505). Thecurrent clinical status of these inhibitors both as monotherapy and incombined therapies (cf. S. T. Wong, Am. J. Health-Syst. Pharm. 2009, 66,S9) as well as the patents describing their main features has beenreviewed (cf. F. Thaler, Pharm. Pat. Analyst 2012, 1, 75; M. L. Curtin,Expert Opin. Ther. Patents 2003, 12, 1375; T. A. Miller, Expert Opin.Ther. Patents 2004, 14, 791; H. Weinmann and E. Ottow, Expert Opin.Ther. Patents 2005, 15, 1677; S. Price and H. J. Dyke, Expert Opin.Ther. Patents 2007, 17, 745; H. Wang and B. W. Dymock, Expert Opin.Ther. Patents 2009, 19, 1727).

In general, HDACi possess common structural features like a relativelybulky capping group—that is intended to lie at the rim of the tunnelthat connects the environment of the enzyme with the active site—anspacer—that mimics the side chain of the lysine residue and occupies thetunnel—and a chelating group that binds the Zn (II) metallic center ofthe active site (cf. A. Villar-Garea and M. Esteller, Int. J. Cancer2004, 112, 171). Very recently HDACi that lack this latter chelatinggroup have been described (cf. C. J. Vickers et al. ACS Med. Chem. Left.2012, 3, 505).

The chelating metal-binding moieties usually present in HDACi arehydroxamic acids and other groups like thiols and disulfides (the latterprobably giving rise in vivo to the corresponding thiolates), epoxidesand benzamides (cf. T. Suzuki and N. Miyata, Curr. Med. Chem. 2005, 12,2867)

Among the capping groups, cyclic peptides and related derivatives,1H-indoles (cf. Y. Dai et al. Bioorg. Med. Chem. Lett. 2003, 13, 1897),1H-pyrroles (cf. A. Zubia et al. Oncogene 2008, 28, 1477), aromaticgroups (cf. E. Pontiki and D. Hadjipavlou-Litina, Med. Res. Rev. 2011,32, 165) and tricyclic systems likedibenzo[b,t][1,4]thiazepin-11(10H)-ones and related O- and N-analogs(cf. M. Blnaschi et al. ACS Med. Chem. Lett. 2010, 1, 411) have beendescribed as convenient components of HDACi.

WO2010/028192 describes 6-aminohexanoic acid derivatives as HDACinhibitors having an aryl or heteroaryl as capping group, an amidelinker and a heterocycloalkyl, aryl or heteroaryl group as chelatingmoiety, which are reported to be used for the treatment of cancer,inflammatory disorders, neurological conditions and malaria.

WO2010/131922 discloses compounds having a structure comprising a linkerbased on an amide group and a phenylamine moiety, but which findapplication for bone formation and for preventing and treating bonedisorders.

Although different combinations of capping groups, spacers and chelatingmoieties have been prepared and tested, the most convenient combinationof these building blocks is unknown. Thus, the HDACi activity of a newmolecule combining these components cannot be predicted a priori, bothin terms of potency and selectivity among the different HDAC isoforms.Actually, most of the HDACi reported so far are pan-inhibitors, whichcan generate undesired side effects (cf. A. V. Bieliauskas and M. K. H.Pflum, Chem. Soc. Rev. 2008, 37, 1402).

1,2,3,4-Tetrahydroacridin-9-amine (Tacrine) is a centrally actingcholinesterase inhibitor in use for the treatment of Alzheimer'sdisease. Other acridins have been prepared and tested within the sametherapeutic field (cf. V. Tumiatti et al. Curr. Med. Chem. 2010, 17,1825). Furthermore, tacrine hybrids, such as tacrine-melatonin andtacrine-E2020 (a N-benzylpiperidine based AChE inhibitor), have alsobeen reported for the treatment of Alzheimer disease (Rodriguez-Francoet al., J. Med. Chem., 2006, 49, 459-462; Shao et al., Bioorganic &Medicinal Chemistry Letters, 2004, 14, 4639-4642). Acridin (cf. L.Gupta, M. S. Chauhan, Chem. & Biol. Interface, 2011, 1, 1, 1-43) ortetrahydroacridin derivatives reported in the field of oncology arescarce. Thus, several amidoacridine derivatives have been described asselective inhibitors of ubiquitin specific protease 7 (cf. R. Lopez andF. Coland, Eur. Pat. Appl. 2011, EP2357176 A1, WO 2011/986178 A1).Likewise, a number of acridine and quinoline derivatives have beenreported as sirtuin modulators (cf. M. Milburn et al. PCT Int. Appl.2006 WO 2006094237 A1, US 2009/0069301 A1).

However, to the best of our knowledge, the activity oftetrahydroacridine derivatives and related compounds as HDACi has notbeen reported. In particular, the interaction between these heterocycleswith different spacers and chelating groups in order to generate HDACiactivity is unknown.

OBJECT OF THE INVENTION

A first aspect of the invention refers to compounds of general formula(I),

wherein:X and Y are independently selected from a N atom or a C—R group, whereinR is selected from a hydrogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxylgroup and a hydroxyl group;n is an integer selected from 1, 2 and 3;A is a —NH— group or a —C(O)NH— group;W represents a spacer group selected from —(CH₂)_(m)—, where m is 5 or6, and the group of formula (II):

wherein the dashed lines represent the covalent unions with the groups Aand —C(═O)—NH—Z;Z is selected from a hydroxyl group and a group of formula (III):

wherein:the dashed line represents the covalent union with group W—C(═O)—NH—;X′ is selected from a —CH— group and a N atom; andR′ and R″ are independently selected from a H atom, a C₁-C₆ alkyl group,a C₆-C₁₀ aryl group, optionally substituted with a group selected from aC₁-C₆ alkyl, halogen, nitro, cyano, OR^(a), SR^(a), SOR^(a), SO₂R^(a),NR^(a)R^(b), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(b) or OC(O)R^(a),wherein R^(a) and R^(b) are hydrogen or a C₁-C₆ alkyl group; and aC₅-C₁₀ heteroaryl group having from one to five heteroatoms selectedfrom nitrogen, oxygen and sulfur;or a solvate or a salt thereof.

Likewise, another aspect of the invention refers to the process for thepreparation of compounds of general formula (I), or a solvate or a saltthereof.

Another aspect of the present invention relates to a compound of generalformula (I), or a salt or solvate thereof, for its use as a medicament.

Another aspect of the present invention relates to a compound of generalformula (I), or a salt or solvate thereof, for its use in the treatmentof cancer, hematological malignancy, proliferative diseases,neurological disorders and immunological disorders.

Another aspect of the present invention relates to the use of a compoundof general formula (I), or a salt or solvate thereof, in the preparationof a medicament for the treatment of cancer, hematological malignancyand proliferative diseases, proliferative diseases, neurologicaldisorders and immunological disorders.

According to another aspect, the present invention is directed to amethod of treating cancer, hematological malignancy, proliferativediseases, neurological disorders and immunological disorders, whichcomprises the administration to a patient needing such treatment, of atherapeutically effective amount of at least one compound of generalformula (I) or a salt or solvate thereof.

A further object of the invention is a pharmaceutical compositioncomprising at least one compound of general formula (I), or a salt orsolvate thereof, and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

First, the present invention provides compounds of general formula (I),

wherein:X and Y are independently selected from a N atom or a C—R group, whereinR is selected from a hydrogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxygroup and a hydroxy group;n is an integer selected from 1, 2 and 3;A is a —NH— group or a —C(O)NH— group;W represents a spacer group selected from —(CH₂)_(m)—, where m is 5 or6, and the group of formula (II):

wherein the dashed lines represent the covalent unions with the groups Aand —C(═O)—NH—Z;Z is selected from a hydroxy group and a group of formula (III):

wherein:the dashed line represents the covalent union with group W—C(═O)—NH—;X′ is selected from a —CH— group and a N atom; andR′ and R″ are independently selected from a H atom, a C₁-C₆ alkyl group,a C₆-C₁₀ aryl group, optionally substituted with a group selected from aC₁-C₆ alkyl, halogen, nitro, cyano, OR^(a), SR^(a), SOR^(a), SO₂R^(a),NR^(a)R^(b), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(b) or OC(O)R^(a),wherein R^(a) and R^(b) are hydrogen or a C₁-C₆ alkyl group; and aC₅-C₁₀ heteroaryl group having from one to five heteroatoms selectedfrom nitrogen, oxygen and sulfur;or a solvate or a salt thereof.

The term “C₁-C₆ alkyl” refers to a linear or branched hydrocarbon chainradical consisting of carbon and hydrogen atoms, containing nounsaturation, having 1 to 6 carbon atoms, which is attached to the restof the molecule by a single bond. Exemplary alkyl groups can be methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert-butyl.

The term “C₁-C₆ alkoxyl” refers to a radical of the formula —O—C₁-C₆alkyl, wherein “C₁-C₆ alkyl” is as defined above. In an embodiment ofthe invention, alkoxyl refers to a radical of formula —O—C₁-C₃ alkyl.Exemplary alkoxyl radicals are methoxyl, ethoxyl, n-propoxyl ori-propoxyl.

The term “C₆-C₁₀ aryl” refers to a C₆-C₁₀ aromatic group comprising 1, 2or 3 aromatic rings, linked by a carbon-carbon bond or condensed,optionally substituted with a group selected from a C₁-C₆ alkyl,halogen, nitro, cyano, OR^(a), SR^(a), SOR^(a), SO₂R^(a), NR^(a)R^(b),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(b) or OC(O)R^(a), wherein R^(a) andR^(b) are hydrogen or an alkyl group as defined above. The term arylincludes for example, and in a non-limiting sense, phenyl, naphthyl,biphenyl, indenyl, etc.

The term “C₅-C₁₀ heteroaryl” refers to a stable 5 to 10 memberedaromatic ring, preferably a 5 or 6 membered aromatic ring, whichconsists of carbon atoms and from one to five heteroatoms selected fromnitrogen, oxygen and sulfur. For the purposes of this invention, theheteroaryl radical may be a monocyclic, bicyclic or tricyclic ringsystem, which may include condensed ring systems; and nitrogen, carbonor sulfur atoms in the heteroaryl radical may be optionally oxidized;and the nitrogen atom may be optionally quaternized. Examples of suchheteroaryl include, but are not limited to, benzimidazole,benzothiazole, furan, thiophene, pyrrole, pyridine, pyrimidine,isothiazole, imidazole, indole, purine, quinoline, thiadiazole.

In a particular embodiment, at least one of X and Y is —C—R—, preferablyboth X and Y are —C—R—, wherein R is selected from hydrogen, a C₁-C₄alkyl, a C₁-C₄ alkoxyl and a hydroxyl group. Preferably, R is selectedfrom hydrogen, hydroxyl and a C₁-C₄ alkoxyl group, even more preferablyR is hydrogen.

In another particular embodiment, W is —(CH₂)_(n)—, wherein n is aninteger selected from 5 and 6.

In another particular embodiment, A is —NH—.

In a particular embodiment, Z is selected from a hydroxyl group and agroup of formula (III):

-   -   wherein:    -   X′ is selected from a —CH— group and a N atom;    -   R′ is selected from a C₁-C₆ alkyl group; a C₆-C₁₀ aryl group,        optionally substituted with a C₁-C₆ alkyl group; and a C₅-C₆        heteroaryl group having from 1 to 3 N atoms;    -   R″ is a C₁-C₆ alkyl group.

In a preferred embodiment, Z is a hydroxyl group.

In another preferred embodiment, the compounds of general formula (I)are selected from:

-   [1] N-Hydroxy-6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexanamide,    with the following structural formula:

-   [2] N-Hydroxy-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [3]    7-{(2,3-dihydro-1H-cyclopenta[b]quinolyl)amino}-N-hydroxyheptanamide,    with the following structural formula:

-   [4]    N-Hydroxy-7-{(7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino}heptanamide,    with the following structural formula:

-   [5]    N-Hydroxy-7-[(5-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [6]    N-Hydroxy-7-[(5-hydroxy-1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [7]    N-Hydroxy-7-{(6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-5-yl)amino}heptanamide,    with the following structural formula:

-   [8]    N-Hydroxy-7-{(6,7,8,9-tetrahydrobenzo[b][1,7]naphthyridin-5-yl)amino}heptanamide,    with the following structural formula:

-   [9]    N-Hydroxy-4-{[(1,2,3,4-tetrahydroacridin-9-yl)amino]methyl}benzamide,    with the following structural formula:

[10]N-[6-(hydroxyamino)-6-oxohexyl]-1,2,3,4-tetrahydroacridine-9-carboxamide,with the following structural formula:

-   [11]    N-[7-(hydroxyamino)-7-oxoheptyl]-1,2,3,4-tetrahydroacridine-9-carboxamide,    with the following structural formula:

-   [12]    N-(2-Amino-4-methylphenyl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [13]    N-(2-Amino-5-methylphenyl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [14]    N-[2-Amino-5-(tert-butyl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [15]    N-(4-Amino-[1,1′-biphenyl]-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [16]    N-(4-Amino-[1,1′-biphenyl]-3-yl)-6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexanamide,    with the following structural formula:

-   [17]    N-(4-Amino-3′-methyl-[1,1′-biphenyl]-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [18]    N-{4-Amino-4′-(tert-butyl-[1,1′-biphenyl]-3-yl}-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [19]    N-[2-Amino-5-(naphthalen-2-yl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [20]    N-(2-Amino-5-phenylpyridin-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

-   [21]    N-[2-Amino-5-(pyridin-3-yl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,    with the following structural formula:

or a solvate or a salt or prodrug thereof.

The compounds of formula (I) defined above may be in the form ofsolvates or salts or prodrugs, preferably as a pharmaceuticallyacceptable species.

The term “pharmaceutically acceptable species” refers to compositionsand molecular entities that are physiologically tolerable and do nottypically produce an allergic reaction or a similar unfavorable reactionas gastric disorders, dizziness and suchlike, when administered to ahuman or animal. Preferably, the term “pharmaceutically acceptable”means it is approved by a regulatory agency of a state or federalgovernment or is included in the U.S. Pharmacopoeia or other generallyrecognized pharmacopoeia for use in animals, and more particularly inhumans.

The term “solvate” means any form of the active compound of theinvention which has another molecule (for example a polar solvent suchas water or ethanol, a cyclodextrin or a dendrimer) attached to itthrough noncovalent bonds. Methods of solvation are known within theart.

The invention also provides salts of the compounds of the invention.Non-limiting examples are sulphates; hydrohalide salts; phosphates;lower alkane sulphonates; arylsulphonates; salts of C₁-C₂₀ aliphaticmono-, di- or tribasic acids which may contain one or more double bonds,an aryl nucleus or other functional groups such as hydroxy, amino, orketo; salts of aromatic acids in which the aromatic nuclei may or maynot be substituted with groups such as hydroxyl, lower alkoxyl, amino,mono- or di-lower alkylamino sulphonamido. Also included within thescope of the invention are quaternary salts of the tertiary nitrogenatom with lower alkyl halides or sulphates, and oxygenated derivativesof the tertiary nitrogen atom, such as the N-oxides. In preparing dosageformulations, those skilled in the art will select the pharmaceuticallyacceptable salts.

Solvates, salts and prodrugs can be prepared by methods known in thestate of the art. Note that the non-pharmaceutically acceptable solvatesand prodrugs also fall within the scope of the invention because theycan be useful in preparing pharmaceutically acceptable salts, solvatesor prodrugs.

The compounds of the invention also seek to include compounds thatdiffer only in the presence of one or more isotopically enriched atoms.For example, compounds having the present structures except for thereplacement of a hydrogen by a deuterium or tritium, or the replacementof a carbon by a carbon enriched in ¹¹C, ¹³C or ¹⁴C or a ¹⁵N enrichednitrogen are within the scope of this invention.

Synthesis of Compounds of Formula (I)

Another aspect of the invention refers to procedures to obtain compoundsof general formula (I). The following methods A, B, C and D describesuitable procedures to obtain compounds of formula (Ia), (Ib), (Ic) andI(d), respectively, or solvates or salts or prodrugs thereof.

Compounds of formula (Ia) correspond to compounds of formula (I),wherein X, Y, W and n have the meaning given above, A is NH and Z is OH.

Compounds of formula (Ib) correspond to compounds of formula (I),wherein X, Y, W and n have the meaning given above, A is NH and Z is a2′-aminoaryl or 2′-aminoheteroaryl group in the form described bystructure (III):

wherein X′, R′ and R″ have the meaning given above.

Compounds of formula (Ic) correspond to compounds of formula (I),wherein X, Y, W and n have the meaning given above, A is C(O)NH and Z isOH.

Compounds of formula (Id) correspond to compounds of formula (I),wherein X, Y, W and n have the meaning given above, A is C(O)NH and Z isa 2′-aminoaryl or 2′-aminoheteroaryl group in the form described bystructure (III) above, wherein X′, R′ and R″ have the meaning givenabove.

Method A

Method A describes the procedure for obtaining compounds of generalformula (Ia),

wherein X, Y, n and W have the meaning given above,which comprises:

-   -   a) reacting an amino acid of general formula (IV),

-   -   wherein X and Y have the meaning given above;    -   with a cyclic ketone of general formula (V),

-   -   wherein n has the meaning given above;        -   in the presence of an appropriate chlorination-condensation            reagent,        -   to afford a compound of formula (VI):

-   -   wherein X, Y and n have the meaning given above;    -   b) reacting the compound of formula (VI) with an ester of        general formula X⁻H₃N⁺—W—COOR′″, wherein W has the meaning        indicated above, R′″ is a linear or branched C₁-C₆ alkyl group,        and X⁻ is an organic or inorganic anion,        -   in the presence of an organic base, and an appropriate            solvent,        -   to afford a compound of formula (VII):

-   -   wherein X, Y, n, W and R′″ have the meaning given above;    -   c) reacting the compound of formula (VII) with hydroxylamine        hydrochloride, in the presence of a liquid alcohol, a solution        of a metallic alkoxide in the previously indicated alcohol, and        an acid-base indicator.

For the aims of the invention, the reaction mixture of step a) can bemade by adding one of the compounds of formula (IV) and (V) to the otherand cooling to 0-5° C. The chlorination-condensation reagent can beadded dropwise at 0-5° C. and the resulting mixture can be heated at atemperature comprised between +100° C. and +185° C. until completion ofthe reaction.

As chlorination-condensation reagent, the use of phosphorous oxychloride(phosphoryl chloride) is preferred.

Compound (VI) can be isolated by evaporation at reduced pressure andaddition of an organic solvent such as ethyl acetate, followed bybasification by means of an adequate inorganic base. This inorganic basemay be selected from the group consisting of carbonates of alkalinemetals or alkaline earth metals (e.g. sodium, lithium, potassium,calcium, or magnesium carbonate), bicarbonates of alkaline metals (e.g.sodium, lithium or potassium bicarbonate), sulfates of alkaline metalsor alkaline earth metals (e.g. sodium, lithium, potassium, calcium, ormagnesium sulfate), acetates of alkaline metals or alkaline earth metals(e.g. sodium, lithium, potassium, calcium, or magnesium acetate),hydroxides of alkaline metals or alkaline earth metals (e.g. sodium,lithium, potassium, calcium, or magnesium hydroxide) or phosphates,monohydrogen phosphates or dihydrogen phosphates of alkaline metals oralkaline earth metals (e.g. sodium, lithium, potassium, calcium, ormagnesium phosphate, or potassium dihydrogen phosphate).

Separation and dehydration of the organic phase, followed by evaporationof the organic solvent, yields compound (VI) which can be used as suchin next step b).

In step b) of the Method A, the compound of formula (VI) is reacted withan ester of formula X—H₃N+-W—COOR′″, wherein W has the meaning indicatedabove, R′″ is a linear or branched C₁-C₆ alkyl group, and X— is anorganic or inorganic anion, in the presence of an organic base and anappropriate solvent.

In a preferred embodiment, R′″ is selected from methyl, ethyl andtert-butyl.

Examples of organic or inorganic anion X— include halide, sulfate,perchlorate, acetate, tartrate or other carboxylic acid.

Step b) can be made by adding the organic base and the solvent on amixture of compound of formula (VI) and the ester at room temperature.After completion of the addition, the resulting mixture can be stirredand heated either by external thermal heating or by microwaveirradiation at a temperature ranging from +60° C. to +145° C. untilcompletion of the reaction.

The organic base may be a primary, secondary or tertiary amine,preferably a tertiary amine selected from among the cyclic or acyclicaliphatic amines with C₃-C₁₀ carbon atoms and the alkanoaromatic amineswith C₉-C₁₅ carbon atoms, more preferably N,N-dimethylaniline,triethylamine, N,N-diisopropyl ethylamine (DIPEA), N-methyl morpholine,N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) andpyridine.

The solvent can be a nonpolar solvent such as a linear or branchedaliphatic hydrocarbon of C₆-C₁₀ carbons or an aromatic hydrocarbon suchas toluene, xylene (any mixture of isomers) or similar.

After standard work-up, the resulting ester of formula (VII) can beisolated and transformed into the corresponding hydroxamic acid offormula (Ia) according to step c).

Said step c) can be performed by adding one of the hydroxylaminehydrochloride, the liquid alcohol and the acid-base indicator to amixture formed by the other two components at a temperature ranging from0° C. to +30° C. After completion of the addition, an aliquot of thealcoholic solution of the metallic alkoxide taken from a stock solutionis added drowpwise until the acid-base indicator changes its color thusshowing a basic pH in the resulting reaction mixture. To this lattermixture the ester (VII) and the alcoholic solution of the metal alcoxidein excess are added and the resulting mixture is stirred at atemperature ranging from 0° C. to +30° C. until the completion of thereaction.

The alcohol can be selected among any alkyl alcohol liquid at roomtemperature and the acid-base indicator can be any compound whose changein color permits to detect unambiguously a basic pH under the indicatedreaction conditions. Suitable examples are phenolphthalein,thymolphthalein, thymol blue, nile blue, diazo violet, bromocresolpurple, dimethyl yellow, and similar compounds.

The synthetic route mentioned above is outlined in the following scheme:

Method B

Method B represents a procedure for the preparation of compounds ofgeneral formula (Ib):

wherein X, Y, n and W have the meaning given in the description ofMethod A and above, and X′, R′ and R″ have the meaning given above,which comprises:

-   -   a) reacting an ester of general formula (VII) prepared according        to Method A,

-   -   wherein X, Y, n and W have the meaning given above, and R′″ has        the meaning given in Method A,        -   with an inorganic hydroxide dissolved or suspended in the            appropriate volume of water, in the presence of a polar            protic solvent,        -   to afford a compound of formula (VIII):

-   -   wherein X, Y, n and W have the meaning given above;    -   b) reacting the compound of formula (VIII) with a protected        diamine of general formula (IX),

-   -   wherein        -   X′, R′ and R″ have the meaning given above;        -   R″″ is a tert-butyl, a benzyl or a 9-fluorenemethyl group,        -   in the presence of an organic base, a coupling reagent, and            an appropriate solvent,        -   to afford the compound of formula (X):

-   -   wherein the meaning of X, Y, n, W, X′, R′, R″ and R″″ are given        above,    -   c) deprotecting the compound of formula (X) in the presence of        an appropriate deprotecting agent and an appropriate solvent, to        afford the compound of formula (Ib).

For the aims of the invention, the reaction of step a) can be made bymixing in any order the different reactants at a temperature rangingfrom 0° C. to +25° C. The resulting mixture is stirred at a temperatureranging from +80° C. to +120° C. until the completion of the reaction.

The polar protic solvent can be selected among any liquid alcohol atroom temperature. The inorganic hydroxide can be selected among theusual alkaline metals such as lithium, sodium or potassium.

The obtained carboxylic acid of formula (VIII) is subjected to acoupling reaction in step b). Said step can be carried out by mixing inany order the different compounds (compound of formula (VIII), compoundof formula (IX), organic base, coupling reagent and solvent) under inertatmosphere and at a temperature ranging from 0° C. to +30° C. Theresulting mixture is stirred for 8-24 hours at a temperature comprisedin the range from +10° C. to +30° C.

The organic base can be selected among a primary, secondary or tertiaryamine, preferably a tertiary amine selected from among the cyclic oracyclic aliphatic amines with C₃-C₁₀ carbon atoms and the alkanoaromaticamines with C₉-C₁₅ carbon atoms, more preferably N,N-dimethylaniline,triethylamine, N,N-diisopropyl ethylamine (DIPEA), N-methyl morpholine,N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) andpyridine.

The coupling reagent can be selected among amide coupling reagents suchas 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), propylphosphonic anhydride (T3P),(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate∥(BOP).

The solvent can be a polar nonprotic solvent such a cyclic or acyclicether, N,N-dimethylformamide or 1,2-dimethoxyethane.

The product of the above indicated reaction is a protected benzamide ofgeneral formula (X).

The final step leading to the preparation of compounds of generalformula (Ib), step c), comprises the deprotection of the compound offormula (X) by reacting said compound with an appropriate deprotectingreagent in the presence of an appropriate solvent.

This step c) can be made by mixing the compound of formula (X) and thesolvent at a temperature ranging from 0° C. to +30° C. To this mixture,the deprotecting reagent can be added at a temperature ranging from 0°C. to +30° C. and the resulting mixture is stirred until completion ofthe deprotection reaction.

The solvent can be a polar protic solvent such an alcohol, like ethanolor other liquid alcohol at room temperature, a polar nonprotic solventsuch a cyclic or acyclic ether, N,N-dimethylformamide, dichloromethane,1,2-dichloroethane, 1,2-dimethoxyethane or similar.

The suitable deprotecting reagent can vary depending on the nature ofthe carbamate moiety present in the compound of formula (X). If R″″ is atert-butyl group (C(═O)OR″″ being a Boc group) the deprotecting reagentcan be a suitable acid such as trifluoroacetic acid or similar; if R″″is a benzyl group (C(═O)OR″″ being a Cbz group) the deprotecting reagentis a hydrogenation system formed by hydrogen gas in the presence of asuitable heterogeneous or homogeneous catalyst such as Pd/C or similar;if R″″ is a 9-fluorenemethyl group (C(═O)OR″″ being a Fmoc group) thedeprotecting reagent is a suitable base such as piperidine or similar.

The synthetic route mentioned above is outlined in the following scheme:

Method C

Method C represents a procedure for the preparation of compounds ofgeneral formula (Ic):

wherein X, Y, n and W have the meaning given above,which comprises:

-   -   a) reacting a compound of formula (XI),

-   -   wherein X, Y and n have the meaning given above;        -   with an ester of general formula X⁻H₃N⁺—W—COOR′″, wherein W,            R′″ and X⁻ have the meaning indicated in Method A, in the            presence of an organic base, a coupling reagent, and an            appropriate solvent,        -   to afford a compound of formula (XII):

-   -   wherein X, Y, n, W and R′″ have the meaning given above; and    -   b) reacting the compound of formula (XII) with hydroxylamine        hydrochloride, in the presence of a liquid alcohol and a        solution of a metallic alkoxide in the previously indicated        alcohol and an acid-base indicator.

For the aims of the invention, the reaction of step a) can be made bymixing in any order the different reactants (compound of formula (XI),the ester, the organic base, the coupling agent and the solvent) at atemperature ranging from −85° C. to +30° C. The resulting mixture isstirred for 8-24 hours at a temperature comprised in the range from +0°C. to +30° C.

The organic base can be selected among a primary, secondary or tertiaryamine, preferably a tertiary amine selected from among the cyclic oracyclic aliphatic amines with C₃-C₁₀ carbon atoms and the alkanoaromaticamines with C₉-C₁₅ carbon atoms, more preferably N,N-dimethylaniline,triethylamine, N,N-diisopropyl ethylamine (DIPEA), N-methyl morpholine,N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) andpyridine.

The coupling reagent can be selected among amide coupling reagents suchas oxalyl chloride, phenyl dichlorophosphate, diethyl cyanophosphonate(DEPC), or the 1-hydroxybenzotriazole (HOBt) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) system,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), propylphosphonic anhydride (T3P),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP).

The solvent can be a polar nonprotic solvent such a cyclic or acyclicether, N,N-dimethylformamide or 1,2-dimethoxyethane.

After standard work-up, the ester (XII) can be isolated and transformedinto the corresponding hydroxamic acid of formula (Ic) according to stepb).

Said step b) can be performed by adding one of the hydroxylaminehydrochloride, the liquid alcohol and the acid-base indicator to amixture formed by the other two components at a temperature ranging from0° C. to +30° C. After completion of the addition, an aliquot of thealcoholic solution of the metallic alkoxide taken from a stock solutionis added drowpwise until the acid-base indicator changes its color thusshowing a basic pH in the resulting reaction mixture. To this lattermixture the ester (XII) and the alcoholic solution of the metal alcoxidein excess are added and the resulting mixture is stirred at atemperature ranging from 0° C. to +30° C. until the completion of thereaction.

The alcohol can be selected among any alkyl alcohol liquid at roomtemperature and the acid-base indicator can be any compound whose changein color permits to detect unambiguously a basic pH under the indicatedreaction conditions. Suitable examples are phenolphthalein,thymolphthalein, thymol blue, nile blue, diazo violet, bromocresolpurple, dimethyl yellow, and similar compounds.

The synthetic route mentioned above is outlined in the following scheme:

Method D

Method D represents a procedure for the preparation of compounds ofgeneral formula (Id):

wherein X, Y, n and W have the meaning given in the description ofMethod A and above, and X′, R′ and R″ have the meaning given in thedescription of Method B,which comprises:

-   -   a) reacting an ester of general formula (XII) prepared according        to Method C, with an inorganic hydroxide dissolved or suspended        in the appropriate volume of water, in the presence of a polar        protic solvent, to afford the compound of formula (XIII):

-   -   wherein X, Y, n and W have the meaning given above;    -   b) reacting a compound of formula (XIII) with a protected        diamine of general formula (IX):

-   -   wherein        -   X′, R′ and R″ have the meaning given above; and        -   R″″ is a tert-butyl, a benzyl or a 9-fluorenemethyl group,        -   in the presence of an organic base, a coupling reagent, and            an appropriate solvent, to afford the compound of formula            (XIV):

-   -   wherein X, Y, n, W, X′, R′, R″ and R″″ have the meaning given        above;    -   c) deprotecting the compound of formula (XIV) in the presence of        an appropriate deprotecting agent and an appropriate solvent, to        afford the compound of formula (Id).

For the aims of the invention, the reaction of step a) can be made bymixing in any order the different reactants (compound of formula (XII),the inorganic hydroxide dissolved or suspended in water and the polarsolvent) at a temperature ranging from 0° C. to +25° C. The resultingmixture is stirred at a temperature ranging from +80° C. to +120° C.until the completion of the reaction.

The polar protic solvent can be selected among any liquid alcohol atroom temperature. The inorganic hydroxide can be selected among theusual alkaline metals such as lithium, sodium or potassium.

The obtained carboxylic acid of formula (XIII) is subjected to acoupling reaction in step b). Said step can be carried out by mixing inany order the different components (the compound of formula (XIII), thecompound of formula (IX), the organic base, the coupling agent and thesolvent) under inert atmosphere and at a temperature ranging from 0° C.to +30° C. The resulting mixture is stirred for 8-24 hours at atemperature comprised in the range from +10° C. to +30° C.

The organic base can be selected among a primary, secondary or tertiaryamine, preferably a tertiary amine selected from among the cyclic oracyclic aliphatic amines with C₃-C₁₀ carbon atoms and the alkanoaromaticamines with C₉-C₁₅ carbon atoms, more preferably N,N-dimethylaniline,triethylamine, N,N-diisopropyl ethylamine (DIPEA), N-methyl morpholine,N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) andpyridine.

The coupling reagent can be selected among amide coupling reagents suchas 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), propylphosphonic anhydride (T3P),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP).

The solvent can be a polar nonprotic solvent such a cyclic or acyclicether, N,N-dimethylformamide or 1,2-dimethoxyethane.

The product of the above indicated reaction is a protected benzamide ofgeneral formula (XIV).

The final step leading to the preparation of compounds of generalformula (Id), step c), comprises the deprotection of the compound offormula (XIV) by reacting said compound with an appropriate deprotectingreagent in the presence of an appropriate solvent.

This step c) can be made by mixing the compound of formula (XIV) and thesolvent at a temperature ranging from 0° C. to +30° C. To this mixture,the deprotecting reagent can be added at a temperature ranging from 0°C. to +30° C. and the resulting mixture is stirred until completion ofthe deprotection reaction.

The solvent can be a polar protic solvent such an alcohol, like ethanolor other liquid alcohol at room temperature, a polar nonprotic solventsuch a cyclic or acyclic ether, N,N-dimethylformamide, dichloromethane,1,2-dichloroethane, 1,2-dimethoxyethane or similar.

The suitable deprotecting reagent can vary depending on the nature ofthe carbamate moiety present in the compound of formula (XIV). If R″″ isa tert-butyl group (C(═O)OR″″ being a Boc group) the deprotectingreagent can be a suitable acid such as trifluoroacetic acid or similar;if R″″ is a benzyl group (C(═O)OR″″ being a Cbz group) the deprotectingreagent is a hydrogenation system formed by hydrogen gas in the presenceof a suitable heterogeneous or homogeneous catalyst such as Pd/C orsimilar; if R″″ is a 9-fluorenemethyl group (C(═O)OR″″ being a Fmocgroup) the deprotecting reagent is a suitable base such as piperidine orsimilar.

The synthetic route mentioned above is outlined in the following scheme:

The initial compounds and starting materials, e.g. the compounds offormula (IV), (V) and (IX), are either commercially available or can beobtained following procedures described in the literature. For example,see O. Moradel et al. PCT/US2007/066045 (WO/2007/118137) and L. H. Tsaiet al. PCT/US2009/006355 (WO/2010/065117).

A further embodiment of the invention is a salt or solvate or prodrugthereof of a compound of formula (I). According to a particularembodiment, the salt is a phenoxy salt of alkaline metals or alkalineearth metals. To obtain the salts corresponding to compounds of formula(Ia) and (Ic), the hydroxyl group can be treated with hydroxides ofalkaline metals or alkaline earth metals (e.g. sodium, lithium,potassium, calcium, or magnesium hydroxide) at a temperature rangingfrom 0° C. to +40° C. In an embodiment of the invention the reactiontakes place at room temperature using water as solvent. To obtain thesalts corresponding to compounds of formula (Ib) and (Id), the aminogroup can be treated with organic or inorganic acids. In an embodimentof the invention these acids can be selected among the usual acids ofacceptable pharmacological use. To obtain these salts the amino groupcan be treated directly with the corresponding acid in an appropriatesolvent at a temperature ranging from 0° C. to +30° C. In the productthus formed, the anion associated with the corresponding salt can bechloride, acetate, tartrate, lactate, or similar.

Use of the Compounds of the Invention

According to a particular embodiment, the compounds of general formula(I) are useful for the treatment of various types of cancer,hematological malignancy, proliferative diseases, neurological disordersand immunological disorders, by changing the acetylation pattern ofhistones involved in the mentioned diseases.

According to a particular embodiment, the cancer is selected from breastcancer, chronic myelogenous (or myeloid) leukemia (CML), colorectalcancer, fibrosarcoma, gastric cancer, glioblastoma, kidney cancer, livercancer, lung cancer, melanoma, nasopharyngeal cancer, oral cancer,orthotopic multiple myeloma, osteosarcoma, ovarian cancer, pancreaticcancer, and prostate cancer.

According to an embodiment of the invention the neurological disorder isschizophrenia, fragile X syndrome or Alzheimer.

According to an embodiment of the invention the immunological disorderis proviral latency of human immunodeficiency virus type 1 (HIV-1).

Pharmaceutical Compositions

Another aspect of the present invention refers to a pharmaceuticalcomposition which comprises the compounds of formula (I) of theinvention, or a pharmaceutically acceptable solvate or salt thereof, andat least a pharmaceutically acceptable excipient.

The term “excipient” refers to a vehicle, diluent or adjuvant that isadministered with the active ingredient. Such pharmaceutical excipientscan be sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and similars. Water or salineaqueous solutions and aqueous dextrose and glycerol solutions,particularly for injectable solutions, are preferably used as vehicles.Suitable pharmaceutical vehicles are described in “Remington'sPharmaceutical Sciences” by E. W. Martin, 21^(st) Edition, 2005; or“Handbook of Pharmaceutical Excipients”, Rowe C. R.; Paul J. S.; MarianE. Q., sixth Edition.

Examples of pharmaceutical compositions include any solid composition(tablets, pills, capsules, granules, etc.) or liquid composition(solutions, suspensions or emulsions) for oral, topical or parenteraladministration.

In a preferred embodiment the pharmaceutical compositions are in oraldelivery form. Pharmaceutical forms suitable for oral administration maybe tablets and capsules and may contain conventional excipients known inthe art such as binders, for example syrup, gum arabic, gelatin,sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for examplelactose, sugar, cornstarch, calcium phosphate, sorbitol or glycine;lubricants for the preparation of tablets, for example magnesiumstearate; disintegrants, for example starch, polyvinylpyrrolidone,sodium starch glycolate or microcrystalline cellulose; orpharmaceutically acceptable wetting agents such as sodium laurylsulphate.

Solid oral compositions can be prepared by conventional methods ofblending, filling or preparation of tablets. Repeated blendingoperations can be used to distribute the active ingredient in all thecompositions that use large amounts of fillers. Such operations areconventional in the art. The tablets can be prepared, for example, bydry or wet granulation and optionally can be coated by well knownmethods in normal pharmaceutical practice, in particular using a entericcoating.

Pharmaceutical compositions can also be adapted for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in the appropriate unit dosage form. Suitable excipients suchas fillers, buffering agents or surfactants can be used.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and U.S. Pharmacopoeiasand similar reference texts.

In general, the effective amount of a compound of the invention to beadministered will depend on the relative efficacy of the compoundchosen, the severity of the disorder being treated and the patient'sweight. However, the active compounds will normally be administered oneor more times a day, for example 1, 2, 3 or 4 times daily, with typicaltotal daily doses in the range from 0.01 up to 1000 mg/kg/day.

The compounds of the present invention can be used with at least anotherdrug to provide a combination therapy. This other drug or drugs may bepart of the same composition, or may be provided as a separatecomposition and can be administered at the same time or at differenttimes.

The term “treatment” or “treating” in the context of this document meansadministration of a compound or a formulation according to thisinvention to prevent, improve or eliminate the disease or one or moresymptoms associated with the disease. “Treatment” also encompassespreventing, improving or eliminating the physiological sequelae of thedisease.

In order to facilitate the understanding of the preceding ideas, someexamples of experimental procedures and embodiments of the presentinvention are described below. These examples are merely illustrative.

EXAMPLES General Synthesis Methods Method A a.1) Synthesis of TricyclicCaps

A mixture of the corresponding aminoacid (46.53 mmol) and thecorresponding cyclic ketone (51.70 mmol) under argon atmosphere wascooled to 0° C. Then 38.75 ml of POCl₃ were added dropwise, and theresulting mixture was refluxed for 16 h. Then the crude reactionsolution was evaporated to dryness under reduced pressure. The resultingmixture was poured onto a mixture of ice and water, and ethyl acetatewas added. Then solid Na₂CO₃ was added slowly until basic pH wasreached. The organic layer was decanted and the aqueous phase wasextracted with AcOEt. The combined organic phases were dried over Na₂SO₄and evaporated under reduced pressure, to yield the correspondingproduct with high purity (60-92% yield).

a.2) Synthesis of Linear Spacers

In a round-bottom flask under argon atmosphere methanol (34.4 ml) wasintroduced and cooled down to 0° C., and SOCl₂ (7.26 ml) was addeddropwise. The corresponding aminoacid (34.43 mmol) was added, and themixture was stirred at room temperature for 16 h. Then the crudereaction solution was evaporated to dryness under reduced pressure.

a.3) Coupling of Caps and Spacers Under Classical Heating

To a mixture of the corresponding cap (1.0 mmol) and the correspondingspacer (2.0 mmol) under argon atmosphere, xylene (1 ml) and Et₃N (0.4ml) were added, and the mixture was refluxed for 6 hours. Then, xylenewas evaporated under reduced pressure, and the crude thus obtained waspurified by flash chromatography (silica gel, EtOAc/Hx and MeOH/CH₂Cl₂)to afford the desired product (70-76% yield).

a.4) Coupling of Caps and Spacers Under Microwave Irradiation

A mixture of the corresponding cap (1.0 mmol) and the correspondingspacer (2.0 mmol) was placed in a microwave vessel. Then, EtOH (1 ml)and Et₃N (0.4 ml) were added, and the mixture was irradiated withmicrowaves in a Biotage Initiator focused microwave reactor at 140° C.for 3 hours. Then, ethyl acetate was added, and the organic layer waswashed with water, dried over sodium sulfate, filtered and evaporatedunder reduced pressure. The crude thus obtained was purified by flashchromatography (silica gel, EtOAc/Hx and MeOH/CH₂Cl₂) to afford thedesired product (90-95% yield).

a.5) Synthesis of the Hydroxamic Acids

To a solution of hydroxylamine hydrochloride (3.75 mmol) andphenolphtalein (1 mg) in methanol (80 ml) under inert atmosphere, analiquot of sodium methoxide in methanol (taken from a solution of 0.65g, 12 mmol of sodium methoxide in 3.3 ml of methanol) was added dropwiseuntil a permanent pink color was observed. The corresponding methylester (0.61 mmol) and sodium methoxide in methanol (5.0 mmol, 1.4 ml ofthe previously prepared solution) were subsequently added. The reactionmixture was stirred for 26 h, the formation of a dense precipitate beingobserved. Water (3 ml) was added, and this solution was acidified withglacial acetic acid and extracted with CH₂Cl₂ (3×10 ml). The combinedorganic fractions were dried over Na₂SO₄ and evaporated under reducedpressure, to obtain the corresponding hydroxamic acid (80-95% yield).

Method B b.1) Hydrolysis

A mixture of the corresponding methyl ester (15.5 mmol), ethanol (176ml) and 10% aqueous NaOH (85.8 ml) was refluxed for 45 minutes. Then,solvents were evaporated under reduced pressure, and the crude thusobtained was purified by flash chromatography (silica gel, EtOAc/Hx andMeOH/CH₂Cl₂) to afford the desired product (40-80% yield).

b.2) Synthesis of Benzamide Chelating Groups

To a solution of corresponding aniline (46.1 mmol) and Boc-anhydride(92.2 mmol) in THF (100 ml) stirred at room temperature was added acatalitic amount of 4-(dimethylamino)pyridine (DMAP). The reactionmixture was allowed to stir for 90 min, the solvent was removed in vacuoand the residue was dried under vacuum. The oil thus obtained wasdissolved in THF (46 ml), treated with an aqueous sodium hydroxidesolution (2N, 46 ml) and heated to 65° C. for 18 h. Solid sodiumhydroxide (1.8 g, 46.1 mmol) was added to the reaction mixture andheating was continued for 4 h; then THF was removed in vacuo and ayellow solid precipitated from the aqueous solution. The solid wasfiltered, washed with H₂O and dried under vacuum to afford the N-Bocprotected aniline (Yield 90-99%).

A mixture of the corresponding tert-butyl carbamate (0.62 mmol), thecorresponding boronic acid (0.74 mmol), sodium carbonate (0.93 mmol) andPd(PPh₃)₄ (0.04 mmol) in DME/H₂O (2:1, 5 ml) was vigorously stirred at110° C. under argon atmosphere for 20 h. Then water was added, and theproduct was extracted with ethyl acetate. The combined organic layerswere washed with water, dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 10% EtOAc/Hx) to afford the desired product (89-95% yield).

A mixture of the corresponding nitro compound (4.76 mmol), SnCl₂ (33.32mmol) and DMF (34 ml) was placed in a round bottom flask under argonatmosphere. The mixture was stirred at 50° C. for 1.5 h. Then ethylacetate was added, and the organic layer was washed with water andNa₂CO₃ 10% aqueous solution, dried over sodium sulfate, filtered andevaporated under reduced pressure, yielding the desired product (50%yield, brown solid).

b.3) Coupling of the Benzamide Chelating Group

A mixture of the corresponding carboxylic acid (0.508 mmol), thecorresponding tert-butyl aminecarbamate (0.508 mmol), DIPEA (0.7 ml,4.08 mmol) and HATU (1.14 mmol) in DMF (5 ml) was stirred for 16 h underargon atmosphere. Then solvents were removed by evaporation. The residuewas diluted with EtOAc and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated. The crude thusobtained was purified by flash chromatography (silica gel, 10% EtOAc/Hx)to give the desired product (45-50% yield).

b.4) Deprotection of the Carbamate Moiety

A mixture of the corresponding N-Boc protected compound (0.42 mmol),CH₂Cl₂ (3.22 ml) and TFA (1.05 ml) was stirred at room temperature for16 hours. Then solvents were removed by evaporation. The residue wasdiluted with CH₂Cl₂, and washed with an ice/NaHCO₃ mixture. The organiclayer was dried over sodium sulfate, filtered and concentrated. Thecrude thus obtained was purified by flash chromatography (silica gel,EtOAc/Hx and MeOH/CH₂Cl₂) to obtain the desired product (50-80% yield).

Method C c.1) Coupling of Caps and Spacers

A solution of the corresponding carboxylic acid (2.2 mmol) and thecorresponding spacer (2.2 mmol) in DMF was cooled to 0° C. Triethylamine(1.73 ml, 12.32 mol), 1-hydroxybenzotriazole (0.33 g, 2.42 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.46 g,2.42 mmol) and N-methylmorpholine (0.24 ml, 2.2 mmol) were addedsubsequently, and the mixture was stirred for 2 h at 0° C., and for anadditional 96 h at room temperature. Ethyl acetate (160 ml) was added,and the obtained solution was washed with water (30 ml), Na₂S₂O₃ 1 N (30ml, aqueous solution), water (30 ml), NaHCO₃ (30 ml, saturated aqueoussolution), and NaCl (30 ml, saturated aqueous solution), dried overNa₂SO₄ and evaporated under reduced pressure. The crude thus obtainedwas purified by flash chromatography (silica gel, EtOAc/Hx), to obtainthe desired product (45-63% yield).

c.2) Synthesis of the Hydroxamic Acids

To a solution of hydroxylamine hydrochloride (3.75 mmol) andphenolphtalein (1 mg) in methanol (80 ml) under inert atmosphere, analiquot of sodium methoxide in methanol (taken from a solution of 0.65g, 12 mmol of sodium methoxide in 3.3 ml of methanol) was added dropwiseuntil a permanent pink color was observed. The corresponding methylester (0.61 mmol) and sodium methoxide in methanol (5.0 mmol, 1.4 ml ofthe previously prepared solution) were subsequently added. The reactionmixture was stirred for 26 h, the formation of a dense precipitate beingobserved. Water (3 ml) was added, and this solution was acidified withglacial acetic acid and extracted with CH₂Cl₂ (3×10 ml). The combinedorganic fractions were dried over Na₂SO₄ and evaporated under reducedpressure, to obtain the corresponding hydroxamic acid (80-95% yield).

Method D d.1) Hydrolysis

A mixture of the corresponding methyl ester (15.5 mmol), ethanol (176ml) and 10% aqueous NaOH (85.8 ml) was refluxed for 45 minutes. Then,solvents were evaporated under reduced pressure, and the crude thusobtained was purified by flash chromatography (silica gel, EtOAc/Hx andMeOH/CH₂Cl₂) to afford the desired product (40-80% yield).

d.2) Coupling of the Benzamide Chelating Group

A mixture of the corresponding carboxylic acid (0.508 mmol), thecorresponding tert-butyl aminecarbamate (0.508 mmol), DIPEA (0.7 ml,4.08 mmol) and HATU (1.14 mmol) in DMF (5 ml) was stirred for 16 h underargon atmosphere. Then solvents were removed by evaporation. The residuewas diluted with EtOAc and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated. The crude thusobtained was purified by flash chromatography (silica gel, 10% EtOAc/Hx)to give the desired product (45-50% yield).

d.3) Deprotection of the Carbamate Moiety

A mixture of the corresponding N-Boc protected compound (0.42 mmol),CH₂Cl₂ (3.22 ml) and TFA (1.05 ml) was stirred at room temperature for16 hours. Then solvents were removed by evaporation. The residue wasdiluted with CH₂Cl₂, and washed with an ice/NaHCO₃ mixture. The organiclayer was dried over sodium sulfate, filtered and concentrated. Thecrude thus obtained was purified by flash chromatography (silica gel,EtOAc/Hx and MeOH/CH₂Cl₂) to obtain the desired product (50-80% yield).

Synthesis of Compounds of the Invention Example 1 Preparation ofN-hydroxy-6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexanamide, with thefollowing structural formula

This compound was prepared following procedures described in Method A.m.p. 162-164° C.; IR 3434, 3188, 3008, 1738, 1639, 1560, 1505, 1423,1356, 1274, 1158, 754 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.29 (s,1H), 8.61 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.51(t, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 5.36 (s, 1H), 3.38 (dd,J=13.8 Hz, J′=6.8 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H), 2.71 (t, J=5.7 Hz,2H), 1.91 (t, J=7.3 Hz, 2H), 1.87-1.76 (m, 4H), 1.59-1.51 (m, 2H),1.51-1.43 (m, 2H), 1.26 (dt, J=14.6 Hz, J′=7.3 Hz, 2H); ¹³C-NMR (75 MHz,δ ppm, DMSO-d₆) 169.0, 157.7, 150.5, 146.6, 128.0, 123.3, 123.1, 120.1,115.7, 47.9, 33.3, 32.2, 30.3, 25.9, 25.0, 24.9, 22.7, 22.4. C₁₉H₂₅N₃O₂;MS (ESI, m/z): 328.22 [M+1]⁺.

Example 2 Preparation ofN-hydroxy-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide, with thefollowing structural formula

This compound was prepared following procedures described in Method A.m.p. 156-157° C.; IR 3377, 3184, 1736, 1629, 1560, 1502, 1410, 1357,1292, 1134, 765 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.30 (s, 1H),8.66 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.51 (t,J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 5.34 (t, J=6.4 Hz, 1H), 3.38 (m,2H, signal partially overlapped with broad signal of water at 3.32 ppm,confirmed by COSY), 2.90 (t, J=6.0 Hz, 2H), 2.71 (t, J=5.9 Hz, 2H), 1.90(t, J=7.4 Hz, 2H), 1.86-1.76 (m, 4H), 1.53 (dt, J=15.0 Hz, J′=7.4 Hz,2H), 1.44 (dt, J=14.9 Hz, J′=7.6 Hz, 2H), 1.32-1.16 (m, 4H); ¹³C-NMR(126 MHz, δ ppm, DMSO-d₆) 169.0, 158.0, 150.3, 147.0, 128.4, 127.9,123.2, 123.1, 120.3, 115.9, 48.0, 33.6, 32.2, 30.5, 28.4, 26.1, 25.1,25.1, 22.8, 22.5. C₂₀H₂₇N₃O₂; MS (ESI, m/z): 342.17 [M+1]⁺.

Example 3 Preparation of7-[(2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino]-N-hydroxyheptanamide,with the following structural formula

This compound was prepared following procedures described in Method A.Yield 96%; m.p. 165-166° C.; IR 3371, 3184, 1737, 1631, 1543, 1416,1364, 1026, 759 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.31 (s, 1H),8.62 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.55 (t,J=7.4 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 6.81 (s, 1H), 3.51 (dd, J=13.6Hz, J′=6.6 Hz, 2H), 3.17 (t, J=7.2 Hz, 2H), 2.89 (t, J=7.7 Hz, 2H),2.08-2.00 (m, 2H), 1.92 (t, J=7.4 Hz, 2H), 1.60-1.53 (m, 2H), 1.51-1.45(m, 2H), 1.36-1.31 (m, 2H), 1.29-1.22 (m, 2H); ¹³C-NMR (126 MHz, δ ppm,DMSO-d₆) 169.1, 166.8, 147.3, 146.4, 128.5, 126.9, 123.5, 121.9, 118.5,111.7, 44.0, 33.7, 32.2, 30.7, 30.7, 28.4, 25.9, 25.1, 22.7. C₁₉H₂₅N₃O₂;MS (ESI, m/z): 328.35 [M+1]⁺.

Example 4 Preparation ofN-hydroxy-7-[(7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method A.Yield 62%; m.p. 155-156° C.; IR 3319, 1738, 1632, 1501, 1447, 1350, 766cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.28 (s, 1H), 8.61 (s, 1H), 8.14(d, J=8.1 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.54 (t, J=7.0 Hz, 1H), 7.40(t, J=7.0 Hz, 1H), 5.25 (s, 1H), 3.19 (dd, J=14.0 Hz, J′=6.8 Hz, 2H),3.07-3.05 (m, 2H), 2.92-2.90 (m, 2H), 1.90 (t, J=7.4 Hz, 2H), 1.86-1.80(m, 2H), 1.70-1.63 (m, 4H), 1.58-1.51 (m, 2H), 1.47-1.41 (m, 2H),1.31-1.16 (m, 4H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 169.0, 164.8,150.0, 146.3, 128.5, 127.8, 124.1, 123.1, 122.8, 122.0, 49.8, 32.2,31.5, 30.4, 28.4, 28.1, 27.2, 26.6, 26.2, 25.1. C₂₁H₂₉N₃O₂; MS (ESI,m/z): 357.38 [M+1]⁺.

Example 5 Preparation ofN-hydroxy-7-[(5-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method A.m.p. 361° C.; IR 3376, 3221, 1631, 1578, 1357, 1275, 1233, 740 cm⁻¹;¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.29 (s, 1H), 8.62 (s, 1H), 8.14 (s,1H), 7.79 (d, J=8.4 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.25 (s, 1H), 3.99(s, 3H), 3.61 (s, 2H), 2.98 (s, 2H), 2.67 (s, 2H), 1.91 (t, J=7.4 Hz,2H), 1.85-1.77 (m, 4H), 1.67-1.58 (m, 2H), 1.51-1.40 (m, 2H), 1.32-1.21(m, 4H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 169.2, 164.1, 154.4, 152.5,135.2, 124.0, 119.5, 115.2, 115.0, 108.7, 55.9, 47.8, 32.2, 31.5, 30.3,28.4, 26.0, 25.1, 24.8, 22.3, 21.8. C₂₁H₂₉N₃O₃; MS (ESI, m/z): 372.54[M+1]⁺.

Example 6 Preparation ofN-hydroxy-7-[(5-hydroxy-1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method A.m.p. 73° C.; IR 3329, 1609, 1561, 1449, 1319, 1231, 661 cm⁻¹; ¹H-NMR(500 MHz, δ ppm, DMSO-d₆) 7.67 (d, J=8.3 Hz, 1H), 7.27 (t, J=7.9 Hz,1H), 7.03 (d, J=7.3 Hz, 1H), 3.40 (s, 2H), 2.91 (s, 2H), 2.68 (s, 2H),2.14 (t, J=7.0 Hz, 2H), 1.79 (s, 4H), 1.53 (s, 2H), 1.43 (t, J=5.8 Hz,2H), 1.24 (s, 4H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 174.5, 155.5,153.9, 151.2, 137.3, 123.5, 120.57, 116.0, 114.8, 107.5, 55.5, 47.9,33.7, 30.4, 28.3, 26.0, 24.9, 24.4, 22.5, 22.2. C₂₀H₂₇N₃O₃; MS (ESI,m/z): 358.23 [M+1]⁺.

Example 7 Preparation ofN-hydroxy-7-[(6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-5-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method A.m.p. 234-235° C.; IR 3214, 1738, 1583, 1524, 1440, 1349, 1234, 774 cm⁻¹;¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.29 (s, 1H), 8.81 (d, J=4.2 Hz, 1H),8.55 (d, J=8.5 Hz, 1H), 8.48-8.42 (m, 1H), 7.33 (dd, J=8.3 Hz, J′=4.2Hz, 1H), 5.67 (t, J=5.6 Hz, 1H), signal corresponding to 2H overlappedwith broad signal of water at 3.42 ppm (confirmed by COSY), 2.92 (t,J=5.9 Hz, 2H), 2.69 (t, J=5.7 Hz, 2H), 1.89 (t, J=7.4 Hz, 2H), 1.85-1.79(m, 4H), 1.57-1.52 (m, 2H), 1.50-1.39 (m, 4H), 1.31-1.16 (m, 2H);¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 169.1, 160.8, 154.8, 151.8, 151.4,133.1, 118.6, 115.5, 113.9, 47.9, 33.8, 32.2, 30.4, 28.4, 26.1, 25.1,25.0, 22.6, 22.3. C₁₉H₂₆N₄O₂; MS (ESI, m/z): 343.34 [M+1]⁺.

Example 8 Preparation ofN-hydroxy-7-[(6,7,8,9-tetrahydrobenzo[b][1,7]naphthyridin-5-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method A.Yield 70%; m.p. 56.7° C.; IR 3409, 3221, 1726, 1627, 1543, 1501, 1418,1262, 1159 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.28 (s, 2H), 9.03(s, 1H), 8.61 (s, 1H), 8.32 (d, J=5.7 Hz, 1H), 7.97 (d, J=5.8 Hz, 1H),3.48 (dd, J=13.8, 6.9 Hz, 2H), 2.94 (t, J=6.2 Hz, 2H), 2.70 (t, J=6.0Hz, 2H), 1.93-1.86 (m, 2H), 1.85-1.77 (m, 2H), 1.60-1.51 (m, 2H),1.49-1.41 (m, 2H), 1.31-1.19 (m, 6H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆)169.1, 159.7, 152.8, 148.9, 142.2, 140.2, 122.6, 117.8, 115.9, 47.2,33.6, 32.2, 30.4, 28.3, 25.9, 25.3, 25.1, 22.4, 22.2. C₁₉H₂₆N₄O₂. MS(ESI, m/z): 343.34 [M+1]⁺.

Example 9 Preparation ofN-hydroxy-4-{[(1,2,3,4-tetrahydroacridin-9-yl)amino]methyl}benzamide,with the following structural formula

This compound was prepared following procedures described in Method A.m.p. 204-205° C.; IR 3426, 3378, 3222, 1738, 1631, 1570, 1503, 1438,1351, 1292, 1136, 758, 617 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 8.96(s, 2H), 8.09 (d, J=8.5 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.1Hz, 2H), 7.52 (t, J=7.5 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.30 (t, J=7.7Hz, 1H), 6.27 (s, 1H), 4.68 (d, J=6.1 Hz, 2H), 2.89 (t, J=6.2 Hz, 2H),2.72 (t, J=6.0 Hz, 2H), 1.95-1.62 (m, 4H); ¹³C-NMR (126 MHz, δ ppm,DMSO-d₆) 164.0, 157.4, 150.4, 146.0, 143.8, 131.4, 129.5, 128.4, 127.5,127.0, 126.9, 123.6, 123.0, 119.7, 115.8, 50.5, 32.9, 25.1, 22.6, 22.2.C₂₁H₂₁N₃O₂, MS (ESI, m/z): 348.17 [M+1]⁺.

Example 10 Preparation ofN-[6-(hydroxyamino)-6-oxohexyl]-1,2,3,4-tetrahydroacridine-9-carboxamide,with the following structural formula

This compound was prepared following procedures described in Method C.m.p. 187-188° C.; IR cm⁻¹ 3258, 1666, 1627, 1535, 1495, 1428, 1358,1263, 1169, 764 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.35 (s, 1H),8.68-8.60 (m, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.69-7.66 (m, 1H), 7.64 (d,J=7.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), signal corresponding to 2Hoverlapped with broad signal of water at 3.35 ppm (confirmed by COSY),3.04 (t, J=6.4 Hz, 2H), 2.83 (t, J=6.1 Hz, 2H), 1.97 (t, J=7.4 Hz, 2H),1.92-1.88 (m, 2H), 1.85-1.81 (m, 2H), 1.61-1.50 (m, 4H), 1.41-1.30 (m,2H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 169.0, 166.3, 158.8, 145.7,142.2, 128.7, 128.2, 126.1, 125.8, 124.6, 123.1, 38.6, 33.4, 32.2, 28.7,26.1, 25.9, 24.8, 22.4, 22.1. C₂₀H₂₅N₃O₃; MS (ESI, m/z): 356.13 [M+1]⁺.

Example 11 Preparation ofN-[7-(hydroxyamino)-7-oxoheptyl]-1,2,3,4-tetrahydroacridine-9-carboxamide,with the following structural formula

This compound was prepared following procedures described in Method C.m.p. 185-186° C.; IR 3404, 3265, 3163, 1634, 1540, 1407, 754 cm⁻¹;¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 10.35 (s, 1H), 8.68-8.61 (m, 2H), 7.90(d, J=8.5 Hz, 1H), 7.68-7.63 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), signalcorresponding to 2H overlapped with broad signal of water at 3.39 ppm(confirmed by COSY), 3.03 (t, J=5.9 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H),1.96 (t, J=7.0 Hz, 2H), 1.93-1.87 (m, 2H), 1.85-1.79 (m, 2H), 1.61-1.46(m, 4H), 1.38-1.27 (m, 4H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 169.1,166.3, 158.8, 145.7, 142.2, 128.8, 128.2, 126.1, 125.8, 124.6, 123.2,38.7, 33.4, 32.3, 28.9, 26.3, 25.9, 25.2, 24.9, 22.4, 22.1. C₂₁H₂₇N₃O₃;MS (ESI, m/z): 370.13 [M+1]⁺.

Example 12 Preparation ofN-(2-amino-4-methylphenyl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 63-64° C.; IR 3326, 3174, 3061, 1719, 1651, 1568, 1379, 1227, 1091,712, 621 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 8.98 (s, 1H), 8.20 (d,J=8.6 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 7.41 (t,J=7.4 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.51 (s, 1H), 6.33 (d, J=7.5 Hz,1H), 6.11 (s, 1H), 4.70 (s, 2H), 3.54 (s, 2H), 2.92 (t, J=5.2 Hz, 2H),2.69 (t, J=5.3 Hz, 2H), 2.26 (t, J=7.3 Hz, 2H), 2.14 (s, 3H), 1.88-1.75(m, 4H), 1.66-1.59 (m, 2H), 1.59-1.52 (m, 2H), 1.40-1.27 (m, 4H);¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 171.1, 155.4, 152.1, 143.9, 141.8,134.7, 129.5, 125.3, 125.2, 123.8, 123.7, 121.2, 118.7, 116.9, 116.3,114.3, 47.8, 35.6, 31.7, 30.3, 28.4, 26.1, 25.2, 24.7, 22.3, 21.8, 20.8.C₂₇H₃₄N₄O. MS (ESI, m/z): 431.22 [M+1]⁺.

Example 13 Preparation ofN-(2-amino-5-methylphenyl)-7-((1,2,3,4-tetrahydroacridin-9-yl)amino)heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 204-205° C.; IR 3242, 1682, 1574, 1517, 1415, 1359, 1199, 1127, 758cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.02 (s, 1H), 8.19 (d, J=8.3 Hz,1H), 7.73 (d, J=8.3 Hz, 1H), 7.61 (t, J=7.4 Hz, 1H), 7.40 (t, J=7.4 Hz,1H), 6.96 (s, 1H), 6.70 (d, J=7.9 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 6.06(s, 1H), 4.58 (s, 2H), 3.62-3.49 (m, 2H), 2.92 (t, J=5.3 Hz, 2H), 2.69(t, J=5.2 Hz, 2H), 2.27 (t, J=7.2 Hz, 2H), 2.12 (s, 3H), 1.81 (d, J=4.7Hz, 4H), 1.66-1.51 (m, 4H), 1.37-1.28 (m, 4H); ¹³C-NMR (126 MHz, δ ppm,DMSO-d₆) 171.0, 155.7, 151.9, 144.3, 139.2, 129.3, 126.2, 125.5, 124.7,123.8, 123.7, 123.6, 118.9, 116.1, 114.5, 47.8, 35.7, 31.9, 30.3, 28.4,26.1, 25.3, 24.8, 22.4, 21.8, 20.1. C₂₇H₃₄N₄O. MS (ESI, m/z): 431.22[M+1]⁺.

Example 14 Preparation ofN-[2-amino-5-(tert-butyl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 75-76° C.; IR 3233, 1648, 1499, 1419, 1358, 818, 758 cm⁻¹; ¹H-NMR(500 MHz, δ ppm, DMSO-d₆) 9.13 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.70 (d,J=8.4 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.11 (d,J=1.8 Hz, 1H), 6.93 (dd, J=8.2 Hz, J′=1.9 Hz, 1H), 6.65 (d, J=8.3 Hz,1H), 5.40 (s, 1H), 4.59 (s, 2H), signal corresponding to 2H overlappedwith broad signal of water at 3.36 ppm (confirmed by COSY), 2.89 (t,J=6.1 Hz, 2H), 2.71 (t, J=5.8 Hz, 2H), 2.26 (t, J=7.3 Hz, 2H), 1.84-1.76(m, 4H), 1.56 (dd, J=13.9 Hz, J′=6.8 Hz, 4H), 1.34-1.28 (s, 4H), 1.19(s, 9H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 171.1, 157.9, 150.5, 146.8,139.4, 138.8, 128.2, 127.9, 123.3, 123.3, 123.1, 122.6, 121.8, 120.2,115.9, 115.8, 48.0, 35.7, 33.5, 31.4, 30.6, 28.5, 26.2, 25.3, 25.1,22.8, 22.5. C₃₀H₄₀N₄O. MS (ESI, m/z): 473.23 [M+1]⁺.

Example 15 Preparation ofN-(4-amino-[1,1′-biphenyl]-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 101-102° C.; IR 3341, 3219, 1667, 1642, 1563, 1516, 1412, 1359,1199, 1127, 759, 698 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.18 (s,1H), 8.38 (d, J=8.6 Hz, 1H), 7.88-7.79 (m, 2H), 7.72-7.61 (m, 1H), 7.56(t, J=8.3 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H), 7.37(t, J=7.7 Hz, 2H), 7.25-7.20 (m, 2H), 6.79 (d, J=8.3 Hz, 1H), 5.02 (s,2H), 3.85 (d, J=6.5 Hz, 2H), 2.97 (s, 2H), 2.66 (s, 2H), 2.34 (t, J=7.3Hz, 2H), 1.82 (s, 4H), 1.78-1.71 (m, 2H), 1.66-1.56 (m, 2H), 1.38 (s,4H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 171.4, 155.7, 150.6, 141.4,140.4, 138.0, 132.7, 128.9, 128.8, 128.0, 126.9, 126.0, 125.5, 125.1,125.0, 123.9, 123.8, 123.2, 119.3, 116.3, 115.5, 111.2, 47.3, 35.7,29.8, 29.6, 28.3, 27.9, 25.9, 25.2, 23.9, 21.5. C₃₂H₃₄N₄O. MS (ESI,m/z): 493.46 [M+1]⁺.

Example 16 Preparation ofN-(4-Amino-[1,1′-biphenyl]-3-yl)-6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 75-76° C.; IR 3341, 3235, 1670, 1635, 1574, 1517, 1414, 1359, 1199,1127, 758, 698 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.12 (s, 1H), 8.30(t, J=9.2 Hz, 1H), 7.76 (s, 2H), 7.66 (d, J=7.9 Hz, 2H), 7.54-7.43 (m,3H), 7.37 (t, 2H), 7.23 (s, 2H), 6.80 (d, J=7.7 Hz, 1H), 4.99 (s, 2H),3.73 (s, 2H), 2.93 (s, 2H), 2.63 (s, 2H), 2.35 (d, J=7.1 Hz, 2H), 1.79(s, 4H), 1.74 (s, 2H), 1.45-1.34 (m, 4H); ¹³C-NMR (126 MHz, δ ppm,DMSO-d₆) 171.2, 155.8, 150.5, 141.2, 140.4, 137.9, 132.7, 129.7, 128.9,128.8, 126.9, 126.8, 126.0, 125.5, 125.2, 125.1, 123.9, 123.2, 119.1,116.2, 115.5, 111.2, 47.2, 35.6, 29.5, 29.1, 27.9, 26.9, 25.6, 21.4,20.3. C₃₁H₃₄N₄O. MS (ESI, m/z): 479.43 [M+1]⁺.

Example 17 Preparation ofN-(4-amino-3′-methyl-[1,1′-biphenyl]-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 53-54° C.; IR 3264, 1742, 1635, 1566, 1516, 1410, 1198, 752 cm⁻¹;¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.12 (s, 1H), 8.12 (d, J=7.9 Hz, 2H),7.70 (d, J=8.2 Hz, 2H), 7.52 (s, 1H), 7.49 (s, 1H), 7.38-7.19 (m, 6H),7.04 (d, J=6.9 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), signal corresponding to2H overlapped with broad signal of water at 3.42 ppm (confirmed byCOSY), 2.90 (d, J=4.2 Hz, 2H), 2.70 (s, 2H), 1.90 (s, 3H), 1.80 (s, 4H),1.58 (s, 4H), 1.35-1.20 (m, 6H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆)171.4, 157.2, 150.51, 141.4, 140.3, 137.8, 130.0, 128.7, 128.3, 127.5,127.0, 126.7, 126.2, 123.9, 123.9, 123.4, 123.3, 122.7, 119.8, 117.9,117.8, 116.3, 47.9, 35.8, 30.5, 28.5, 26.2, 25.2, 25.0, 24.6, 22.7,22.3, 21.2. C₃₃H₃₈N₄O. MS (ESI, m/z): 507.33 [M+1]⁺.

Example 18 Preparation ofN-{4-amino-4′-(tert-butyl)-[1,1′-biphenyl]-3-yl}-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 55-56° C.; IR 3247, 1726, 1643, 1561, 1495, 1414, 1267, 1121, 817,756, 558 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.12 (s, 1H), 8.10 (t,J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.53-7.47 (m, 2H), 7.40 (dd,J=18.5 Hz, J′=8.3 Hz, 4H), 7.32 (t, J=7.6 Hz, 1H), 7.20 (d, J=7.3 Hz,1H), 6.78 (d, J=8.3 Hz, 1H), 4.94 (s, 2H), signal corresponding to 2Hoverlapped with broad signal of water at 3.42 ppm (confirmed by COSY),2.89 (t, J=6.7 Hz, 2H), 2.71 (dd, J=12.8, 7.0 Hz, 2H), 1.85-1.74 (m,4H), 1.63-1.50 (m, 4H), 1.39-1.17 (m, 15H); ¹³C-NMR (126 MHz, δ ppm,DMSO-d₆) 171.2, 157.9, 150.3, 148.3, 146.9, 141.2, 137.5, 131.6, 128.6,128.3, 127.8, 125.5, 125.2, 123.9, 123.7, 123.1, 123.0, 120.3, 116.2,115.9, 47.9, 38.1, 33.5, 31.1, 30.5, 29.8, 28.3, 26.1, 25.1, 23.2, 22.7,22.4. C₃₆H₄₄N₄O. MS (ESI, m/z): 549.37 [M+1]⁺.

Example 19 Preparation ofN-[2-amino-5-(naphthalen-2-yl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 100-101° C.; IR 3232, 1668, 1573, 1415, 1198, 1172, 1124, 813, 751,719 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.22 (s, 1H), 8.36 (d, J=8.6Hz, 1H), 8.00 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.88 (d, J=7.6 Hz, 1H),7.82-7.77 (m, 2H), 7.71 (dd, J=8.5, 1.1 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H),7.57-7.51 (m, 2H), 7.51-7.47 (m, 1H), 7.46-7.43 (m, 1H), 7.40 (dd, J=8.3Hz, J′=2.0 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 5.08 (s, 2H), 3.85-3.76 (m,2H), 2.99-2.91 (m, 2H), 2.68-2.62 (m, 2H), 2.36 (t, J=7.3 Hz, 2H),1.85-1.79 (m, 2H), 1.77-1.70 (m, 2H), 1.67-1.56 (m, 2H), 1.41-1.34 (m,4H), 1.23 (s, 2H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 171.4, 141.7,137.7, 133.5, 131.6, 128.3, 127.8, 127.7, 127.5, 126.3, 125.4, 124.9,124.6, 124.3, 123.9, 123.6, 123.2, 116.3, 47.4, 35.7, 29.8, 29.0, 28.3,25.9, 25.1, 24.0, 21.6, 20.6. C₃₆H₃₈N₄O. MS (ESI, m/z): 543.19 [M+1]⁺.

Example 20 Preparation ofN-(2-amino-5-phenylpyridin-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 49-50° C.; IR 3318, 3222, 1648, 1561, 1498, 1465, 1409, 758, 696cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.13 (s, 1H), 8.13-8.09 (m, 2H),7.97 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.55-7.49 (m, 3H), 7.41(t, J=7.7 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.28 (t, J=7.3 Hz, 1H), 5.91(s, 2H), 5.45 (s, 1H), signal corresponding to 2H overlapped with broadsignal of water at 3.39 ppm (confirmed by COSY), 2.89 (t, J=6.1 Hz, 2H),2.70 (t, J=5.5 Hz, 2H), 2.33 (t, J=7.4 Hz, 2H), 1.80 (dd, J=12.5 Hz,J′=8.3 Hz, 4H), 1.62-1.51 (m, 4H), 1.38-1.26 (m, 4H); ¹³C-NMR (126 MHz,δ ppm, DMSO-d₆) 171.9, 157.7, 153.8, 153.2, 152.4, 152.2, 141.5, 141.1,137.8, 131.0, 128.9, 126.6, 125.6, 124.5, 124.4, 122.5, 118.8, 117.2,112.9, 47.5, 35.8, 30.0, 28.3, 26.0, 25.0, 24.3, 21.9, 21.1. C₃₁H₃₅N₅O.MS (ESI, m/z): 494.16 [M+1]⁺.

Example 21 Preparation ofN-[2-amino-5-(pyridin-3-yl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula

This compound was prepared following procedures described in Method B.m.p. 95-96° C.; IR 3363, 3221, 1637, 1561, 1499, 1465, 1411, 1199, 759,695 cm⁻¹; ¹H-NMR (500 MHz, δ ppm, DMSO-d₆) 9.18 (s, 1H), 8.73 (s, 1H),8.43 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.70 (d,J=8.4 Hz, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.39 (dd,J=7.7 Hz, J′=4.8 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.29 (dd, J=8.3 Hz,J′=1.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 5.46 (s, 1H), 5.12 (s, 2H),signal corresponding to 2H overlapped with broad signal of water at 3.39ppm (confirmed by COSY), 2.89 (t, J=5.7 Hz, 2H), 2.70 (t, J=5.9 Hz, 2H),2.31 (t, J=7.4 Hz, 2H), 1.86-1.72 (m, 4H), 1.64-1.51 (m, 4H), 1.32 (d,J=3.0 Hz, 4H); ¹³C-NMR (126 MHz, δ ppm, DMSO-d₆) 171.4, 157.9, 150.3,147.0, 146.9, 146.7, 142.1, 135.7, 132.7, 128.4, 127.8, 124.6, 124.1,123.9, 123.8, 123.4, 123.2, 123.1, 120.3, 116.3, 115.9, 47.9, 35.8,33.6, 30.5, 28.5, 26.2, 25.2, 25.1, 22.8, 22.5. C₃₁H₃₅N₅O. MS (ESI,m/z): 494.27 [M+1]⁺.

Biological Assays

Example 21 In Vitro Inhibitory Activity of Histone Deacetylase: HumanIsoforms HDAC1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 and HeLa Cell LineNuclear Extract (IC50 Data)

Components of Assay

Substrate Peptides:

All HDAC assays were performed using acetylated AMC-labeled peptidesubstrate:

-   -   Substrate for isoforms HDAC1, 2, 3, 6, 10, 11 and HeLa nuclear        extract assays: Acetylated fluorogenic peptide from p53 residues        379-382 (RHKKAc).    -   Substrate for isoforms HDAC 4, 5, 7, 9: Fluorogenic        Boc-L-Lys(ε-trifluoroacetyl)-AMC.    -   Substrate for HDAC8 assays: Acetylated fluorogenic peptide from        p53 residues 379-382 (RHKAcKAc).

Assay Buffer.

50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂ (supplementwith 1 mg/ml BSA for dilution) (BioMol Cat. # KI-143).

Enzymes:

-   -   HDAC1 assay: 75 nM Human HDAC1 (GenBank Accession No.        NM_004964): Full length with C-terminal GST tag, MW=79.9 kDa,        expressed by baculovirus expression system in Sf9 cells (BioMol        Cat. # SE-456).    -   HDAC2 assay: 5 nM Human HDAC2 (Gen Bank Accession No. Q92769):        Full length with C-terminal His tag, MW=60 kDa, expressed by        baculovirus expression system in Sf9 cells (BioMol Cat. #        SE-500).    -   HDAC3 assay: 2.3 nM Human HDAC3/NcoR2 (GenBank Accession No.        NM_003883 for HDAC3, GenBank Accession No. NM_006312 for NcoR2):        Complex of human HDAC3, full length with C-terminal His tag,        MW=49.7 kDa, and human NCOR2, N-terminal GST tag, MW=39 kDa,        co-expressed in baculovirus expression system (BioMol Cat. #        SE-507).    -   HDAC4 assay: 266 nM Human HDAC4 (GenBank Accession No.        NM_006037): Amino acids 627-1085 with N-terminal GST tag,        MW=75.2 kDa, expressed in baculovirus expression system (BioMol,        Hamburg, Germany).    -   HDAC5 assay: 588 nM Human HDAC5 (GenBank Accession No.        NM_001015053): Full length with Nterminal GST tag, MW=150 kDa,        expressed by baculovirus expression system in Sf9 cells (BioMol,        Hamburg, Germany).    -   HDAC6 assay: 13 nM Human HDAC6 (GenBank Accession No. BC069243):        Full length with N-terminal GST tag, MW=159 kDa, expressed by        baculovirus expression system in Sf9 cells (BioMol Cat. #        SE-508).    -   HDAC7 assay: 962 nM Human HDAC7 (GenBank Accession No.        AY302468): Amino acids 518-end with N-terminal GST tag, MW=78        kDa, expressed in baculovirus expression system (BioMol,        Hamburg, Germany).    -   HDAC8 assay: 119 nM Human HDAC8 (GenBank Accession No.        NM018486): Full length, MW=42 kDa, expressed in an E. coli        expression system (BioMol Cat. # SE-145).    -   HDAC9 assay: 986 nM Human HDAC9 (GenBank Accession No.        NM178423): Amino acids 604-1066 with C-terminal His tag, MW=50.7        kDa, expressed in baculovirus expression system (BioMol,        Hamburg, Germany).    -   HDAC10 assay: 781 nM Human HDAC10 (GenBank Accession No.        NM_032019): Amino acids 1-631 with Nterminal GST tag, MW=96 kDa,        expressed by baculovirus expression system in Sf9 cells (BioMol        Cat. # SE-559).    -   HDAC11 assay: 781 nM Human HDAC11 (GenBank Accession No.        NM_BC009676) with N-terminal GST tag, MW=66 kDa, expressed in        baculovirus expression system (BioMol Cat. # SE-560).    -   HeLaNuclear Extract assay: 25 ng/μl Nuclear Extract from HeLa        Cells: Prepared by high salt extraction of HeLa nuclei (human        cervical cancer cell line), this extract is a rich source of        HDAC activity (BioMol Cat. # KI-140).

Assay Procedure

50 μM of substrate peptide (see ‘substrate peptides’ section above) andan optimal concentration of the corresponding enzyme (see ‘enzymes’section above) in the assay buffer and 1% final concentration of DMSOwere incubated in the presence of gradient concentrations of inhibitors(10-dose IC50 mode with 3-fold serial dilution) at 30° C. for 2 h. Thereactions were carried out in a 96-well microplate for fluorometry in a50 μl reaction volume. After the deacetylation reaction,Fluor-de-Lys-Developer (BioMol Cat. # KI-105) was added to each well todigest the deacetylated substrate, thus producing the fluorescentsignal. The reaction was allowed to develop for 45 minutes at 30° C.with 5% CO₂; then the fluorescent signal was measured with an excitationwavelength at 360 nm and an emission wavelength at 460 nm in amicroplate-reading fluorometer (GeminiXS; Molecular Devices, Sunnyvale,Calif.). A curve of Deacetylated Standard (Biomol, Cat. # KI-142; madefrom 100 μM with 1:2 dilution and 10-doses, 6 μl) allowed the conversionof fluorescent signal into micromoles of deacetylated product. Allexperiments were performed in triplicate. IC50 was calculated by fittingthe experimental data to a dose-response curve. DMSO was used asnegative control; Trichostatin A (Biomol Cat. # GR-309) was used aspositive control inhibitor.

IC50 (μM) Example Example Example 1 Example 2 Example 3 Example 4Example 5 Example 7 Example 8 Example 9 10 11 HDAC-1 2.99 0.36 0.27 0.840.90 1.77 1.12 ND >5 2.95 HDAC-2 6.09 0.75 0.77 1.92 1.84 4.46 2.41ND >5 8.48 HDAC-3 2.84 0.42 0.36 0.74 0.66 2.44 1.88 ND >5 3.62 HDAC-46.19 >5 >5 >5 >5 >5 >5 ND >5 >5 HDAC-5 2.14 0.44 >5 >5 >5 >5 >5 ND >54.24 HDAC-6 0.036 0.01 0 007 0.015 0.015 0.038 0.033 ND 0.33 0.19 HDAC-74.55 0.77 >5 >5 >5 >5 >5 ND >5 >5 HDAC-8 0.59 0.53 1.28 0.84 1.52 1.441.09 ND 0 20 0.21 HDAC-9 2.47 1.57 >5 >5 >5 >5 >5 ND 0 035 3.17 HDAC-105.76 0.71 0.51 1.13 1.46 4.02 2.02 ND >5 6.89 HDAC-11 2.21 0.59 0.441.22 1.04 0.69 0.60 ND >5 4.10 HeLa 0.066 0.023 0.019 0.038 0.033 0.120.095 0.90 0.85 0.42 IC50 (μM) Example Example Example Example ExampleExample Example Example Example 12 13 14 15 17 18 19 20 21 No HDAC-1 >5057.3 >50 1.26 250 46.7 >50 594 3.97 preincubation HDAC-2 >50 62.9 >501.70 188 >50 >50 >50 3.37 HDAC-6 >50 >50 ND 13.15 ND ND ND ND ND HeLa NDND >50 4.68 84.1 429 17.7 >50 78.1 4 h HDAC-1 ND >50 >50 1.48 118 48.1139 >50 8.55 preincubation HDAC-2 ND 54.3 >50 0.079 76.0 65.9 72.7 >502.79 HDAC-6 ND ND ND ND ND ND ND ND ND HeLa ND ND >50 3.99 73.6 25.539.3 109 30.7 ND: not determined

1. A compound of general formula (I),

wherein: X and Y are independently selected from a N atom or a C—Rgroup, wherein R is selected from a hydrogen atom, a C₁-C₆ alkyl group,a C₁-C₆ alkoxyl group and a hydroxyl group; n is an integer selectedfrom 1, 2 and 3; A is a —NH— group or a —C(O)NH— group; W represents aspacer group selected from —(CH₂)_(m)—, where m is 5 or 6, and the groupof formula (II):

wherein the dashed lines represent the covalent unions with the groups Aand —C(═O)—NH—Z; Z is selected from a hydroxyl group and a group offormula (III):

wherein: the dashed line represents the covalent union with groupW—C(═O)—NH—; X′ is selected from a —CH— group and a N atom; and R′ andR″ are independently selected from a H atom; a C₁-C₆ alkyl group; aC₆-C₁₀ aryl group, optionally substituted with a group selected from aC₁-C₆ alkyl, halogen, nitro, cyano, OR^(a), SR^(a), SOR^(a), SO₂R^(a),NR^(a)R^(b), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(b) or OC(O)R^(a),wherein R^(a) and R^(b) are hydrogen or a C₁-C₆ alkyl group; and aC₅-C₁₀ heteroaryl group having from one to five heteroatoms selectedfrom nitrogen, oxygen and sulfur; or a solvate or a salt thereof.
 2. Thecompound according to claim 1, wherein at least one of X and Y is a—C—R— group, wherein R is selected from hydrogen, a C₁-C₄ alkyl, a C₁-C₄alkoxyl and a hydroxyl group.
 3. The compound according to claim 1,wherein both X and Y are a —C—R— group, wherein R is selected fromhydrogen, a C₁-C₄ alkyl, a C₁-C₄ alkoxyl and a hydroxyl group.
 4. Thecompound according to claim 1, wherein W is —(CH₂)_(n)—, wherein n is aninteger selected from 5 and
 6. 5. The compound according to claim 1,wherein A is —NH—.
 6. The compound according to claim 1, wherein Z isselected from a hydroxyl group and a group of formula (III):

wherein: X′ is selected from a —CH— group and a N atom; R′ is selectedfrom a C₁-C₆ alkyl group; a C₆-C₁₀ aryl group, optionally substitutedwith a C₁-C₆ alkyl group; and a C₅-C₆ heteroaryl group having from 1 to3 N atoms; R″ is a C₁-C₆ alkyl group.
 7. The compound according to claim1, wherein Z is a hydroxyl group.
 8. A compound of general formula (I)according to claim 1 selected from the group consisting of: [1]N-Hydroxy-6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexanamide, with thefollowing structural formula:

[2] N-Hydroxy-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide, withthe following structural formula:

[3]7-{(2,3-dihydro-1H-cyclopenta[b]quinolyl)amino}-N-hydroxyheptanamide,with the following structural formula:

[4]N-Hydroxy-7-{(7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino}heptanamide,with the following structural formula:

[5]N-Hydroxy-7-[(5-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[6]N-Hydroxy-7-[(5-hydroxy-1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[7]N-Hydroxy-7-{(6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-5-yl)amino}heptanamide,with the following structural formula:

[8]N-Hydroxy-7-{(6,7,8,9-tetrahydrobenzo[b][1,7]naphthyridin-5-yl)amino}heptanamide,with the following structural formula:

[9]N-Hydroxy-4-{[(1,2,3,4-tetrahydroacridin-9-yl)amino]methyl}benzamide,with the following structural formula:

[10]N-[6-(hydroxyamino)-6-oxohexyl]-1,2,3,4-tetrahydroacridine-9-carboxamide,with the following structural formula:

[11]N-[7-(hydroxyamino)-7-oxoheptyl]-1,2,3,4-tetrahydroacridine-9-carboxamide,with the following structural formula:

[12]N-(2-Amino-4-methylphenyl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[13]N-(2-Amino-5-methylphenyl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[14]N-[2-Amino-5-(tert-butyl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[15]N-(4-Amino-[1,1′-biphenyl]-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[16]N-(4-Amino-[1,1′-biphenyl]-3-yl)-6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexanamide,with the following structural formula:

[17]N-(4-Amino-3′-methyl-[1,1′-biphenyl]-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[18]N-{4-Amino-4′-(tert-butyl-[1,1′-biphenyl]-3-yl}-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[19]N-[2-Amino-5-(naphthalen-2-yl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[20]N-(2-Amino-5-phenylpyridin-3-yl)-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

[21]N-[2-Amino-5-(pyridin-3-yl)phenyl]-7-[(1,2,3,4-tetrahydroacridin-9-yl)amino]heptanamide,with the following structural formula:

or a solvate or a salt or prodrug thereof.
 9. A process for thepreparation of a compound of general formula (I) as defined in claim 1,wherein X, Y, W and n have the meaning given in claim 1, A is NH and Zis OH, which comprises: a) reacting an amino acid of general formula(IV),

wherein X and Y are independently selected from a N atom or a C—R group,wherein R is selected from a hydrogen atom, a C₁-C₆ alkyl group, a C₁-C₆alkoxyl group and a hydroxyl group; with a cyclic ketone of generalformula (V),

wherein n is selected from 1, 2 and 3; in the presence of an appropriatechlorination-condensation reagent, to afford a compound of formula (VI):

wherein X, Y and n have the meaning given above; b) reacting thecompound of formula (VI) with an ester of general formula X⁻H₃N⁺—W—COOR′″, wherein W represents a spacer group selected from—(CH₂)_(m)—, where m is 5 or 6, and the group of formula (II):

wherein the dashed lines represent the covalent unions with the groupsX—H₃N⁺ and —COOR′″; and R′″ is a linear or branched alkyl group, and X⁻is an organic or inorganic anion, in the presence of an organic base,and an appropriate solvent, to afford a compound of formula (VII):

wherein X, Y, n, W and R′″ have the meaning given above; c) reacting thecompound of formula (VII) with hydroxylamine hydrochloride, in thepresence of a liquid alcohol and a solution of a suitable metallicalkoxide in the previously indicated liquid alcohol and an acid-baseindicator.
 10. A process for the preparation of a compound of generalformula (I) as defined in claim 1, wherein X, Y, W and n have themeaning given in claim 1, A is NH and Z is a group of formula (III) asdefined in claim 1, which comprises: a) reacting an ester of generalformula (VII) prepared according to claim 8,

wherein X, Y, n, W and R′″ have the meaning given in claim 8, with aninorganic hydroxide dissolved or suspended in the appropriate volume ofwater, in the presence of a polar protic solvent, to afford a compoundof formula (VIII):

wherein: X and Y are independently selected from a N atom or a C—Rgroup, wherein R is selected from a hydrogen atom, a C₁-C₆ alkyl group,a C₁-C₆ alkoxyl group and a hydroxyl group; and W represents a spacergroup selected from —(CH₂)_(m)—, where m is 5 or 6, and the group offormula (II):

wherein the dashed lines represent the covalent unions with the groupsNH and COOH; b) reacting the compound of formula (VIII) with a protecteddiamine of general formula (IX):

wherein: X′ is selected from a —CH— group and a N atom; and R′ and R″are independently selected from a H atom, a C₁-C₆ alkyl group, a C₆-C₁₀aryl group, optionally substituted with a group selected from a C₁-C₆alkyl, halogen, nitro, cyano, OR^(a), SR^(a), SOR^(a), SO₂R^(a),NR^(a)R^(b), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(b) or OC(O)R^(a),wherein R^(a) and R^(b) are hydrogen or a C₁-C₆ alkyl group; and aC₅-C₁₀ heteroaryl group having from one to five heteroatoms selectedfrom nitrogen, oxygen and sulfur; and R″″ is a tert-butyl, a benzyl or a9-fluorenemethyl group, in the presence of an organic base, a couplingreagent, and an appropriate solvent, to afford the compound of formula(X):

wherein the meaning of X, Y, n, W, X′, R′, R″ and R″″ are given above,c) deprotecting the compound of formula (X) in the presence of anappropriate deprotecting agent and an appropriate solvent.
 11. A processfor the preparation of a compound of general formula (I) as defined inclaim 1, wherein X, Y, W and n have the meaning given in claim 1, A isC(O)NH and Z is OH, which comprises: a) reacting a compound of formula(XI),

wherein X and Y are independently selected from a N atom or a C—R group,wherein R is selected from a hydrogen atom, a C₁-C₆ alkyl group, a C₁-C₆alkoxyl group and a hydroxyl group; and n is selected from 1, 2 and 3;with an ester of general formula X⁻H₃N⁺—W—COOR′″, wherein W, R′″ and X⁻have the meaning indicated in claim 8, in the presence of an organicbase, a coupling reagent, and an appropriate solvent, to afford acompound of formula (XII):

wherein X, Y, n, W and R′″ have the meaning given above; and b) reactingthe compound of formula (XII) with hydroxylamine hydrochloride, in thepresence of a liquid alcohol, a solution of a suitable metallic alkoxidein the previously indicated liquid alcohol, and an acid-base indicator.12. A process for the preparation of a compound of general formula (I)as defined in claim 1, wherein X, Y, W and n have the meaning given inclaim 1, A is C(O)NH and Z is a group of formula (III) as defined inclaim 1, which comprises: a) reacting an ester of general formula (XII)prepared as defined in claim 10, with an inorganic hydroxide dissolvedor suspended in the appropriate volume of water, in the presence of apolar protic solvent, to afford the compound of formula (XIII):

wherein X, Y, n and W have the meaning given in claim 10; b) reacting acompound of formula (XIII) with a protected diamine of general formula(IX):

wherein: X′ is selected from a —CH— group and a N atom; R′ and R″ areindependently selected from a H atom, a C₁-C₆ alkyl group, a C₆-C₁₀ arylgroup, optionally substituted with a group selected from a C₁-C₆ alkyl,halogen, nitro, cyano, OR^(a), SR^(a), SOR^(a), SO₂R^(a), NR^(a)R^(b),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(b) or OC(O)R^(a), wherein R^(a) andR^(b) are hydrogen or a C₁-C₆ alkyl group; and a C₅-C₁₀ heteroaryl grouphaving from one to five heteroatoms selected from nitrogen, oxygen andsulfur; and R″″ is a tert-butyl, a benzyl or a 9-fluorenemethyl group,in the presence of an organic base, a coupling reagent, and anappropriate solvent, to afford the compound of formula (XIV):

wherein X, Y, n, W, X′, R′, R″ and R″″ have the meaning given above; c)deprotecting the compound of formula (XIV) in the presence of anappropriate deprotecting agent and an appropriate solvent. 13.(canceled)
 14. A method for the treatment of a disease or conditionselected from the group consisting of cancer, hematological malignancy,proliferative diseases, neurological disorders and immunologicaldisorders, said method comprises administering to a subject in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) of claim 1, or a pharmaceutically acceptable solvate or asalt thereof.
 15. A pharmaceutical composition that comprises at least acompound of formula (I) of claim 1, or a pharmaceutically acceptablesolvate or a salt thereof, and at least a pharmaceutically acceptableexcipient.